As the prior-art microneedle patch having drug-carrying microprojections, for example, the techniques described in Patent Literature 1 to 8 and Non-patent Literature 1 are known. These pieces of prior art are different from one another in microprojection structures and the methods for loading drugs into microprojections.
The technique of Patent Literature 1 relates to a production method of a microneedle patch and a production apparatus thereof. In this technique, inverted-cone-shaped fine pores are formed in a density of dozens to hundreds per block (1 cm square) on a base of silicone resin or thermoplastic resin, a concentrated solution or a mixture comprising a drug, an additive, a base, or the like is compressed into the pores under pressure and dried during the compression, and the resulting conical projections having a height of 100 to 500 μm and a bottom diameter of 100 to 500 μm are taken off from the pores with an adhesive tape and erected on a patch.
According to the technique of Patent Literature 1, one type of drug is loaded alone or as a mixture with the drug and an additive in each microprojection.
According to the technique of Patent Literature 2, die cavities (recessions for forming microprojections) are loaded with an aqueous solution of water-soluble polymeric substance, the solution is dried and solidified into a microneedle sheet, and the sheet is firmly fixed on a substrate sheet provided with an adhesive layer to produce a microneedle patch. The loading process disclosed therein comprises two steps. In the first step, an aqueous solution of a functional material (drug) is loaded into the die cavities, and in the second step, an aqueous solution of water-soluble polymeric substance is loaded thereonto, resulting in a two-layer microprojections.
However, also in the case of the technique of Patent Literature 2, only one type of drug is loaded in each microprojection.
According to the technique of Patent Literature 3, a microneedle sheet part is molded from a water-soluble resin film based on the technique of Patent Literature 2, and thus time for solidifying and drying is significantly shortened, leading to a reduction in production time and production costs.
One type of drug is loaded in all the microprojections, as is the case with Patent Literature 2.
According to the technique of Patent Literature 4, a plurality of microprojections are formed by etching or punching a thin sheet, and coating with at least one type of useful active substance and at least one type of water-soluble biocompatible carrier is performed on at least a part of each microprojection. When such a microneedle patch is used, the microprojection penetrates through the stratum corneum, the coating comes into contact with body fluid and the useful active substance is absorbed into skin tissue.
The technique of Patent Literature 5 is an apparatus and method for transdermal delivery of an immunologically active substance, comprising a delivery system which has a microprojection array comprising a large number of microprojections designed to perforate the skin through the stratum corneum into the epidermal layer or into the epidermal layer and the dermis layer, which are under the stratum corneum. The microprojection array has a large number of array areas, each array area is provided with a different biocompatible coating, and the coating of at least one array area comprises an immunologically active substance.
That is, each microprojection array area is provided with a different biocompatible coating, allowing the transdermal delivery of a plurality of vaccines and the like.
According to the technique of Patent Literature 6, a microneedle for a preparation 1 for body surface application is composed of the following two parts (a double layered structure): a top part 5 and a bottom part 6. The top part 5 is a part comprising a body surface insertion end 2 and holds a base-soluble objective substance. The bottom part 6 is a part comprising a pressing end 3, mainly consists of a base alone, and holds no objective substance. Since the objective substance is contained in the top part 5, even when the preparation 1 for body surface application is inserted into the body surface such as the skin and a part of the bottom side remains outside the skin without being inserted into the body surface, the actual dose of the objective substance does not become less than the desired amount, and a high absorption ratio and pharmacological effect can be achieved.
In addition, according to the technique disclosed in Patent Literature 6, the microneedle has a multilayer structure comprising two or more layers, and different drugs are loaded in a plurality of intermediate layers.
The technique of Patent Literature 7 is a microneedle having a three-layer structure composed of three parts. Atop part and a bottom part are layers of a water-soluble stringy polymeric substance, which is a base, and the second layer contains a vaccine antigen. When a microneedle is inserted into the skin, the tip part penetrates the dermis of the skin while dissolving. Since the vaccine antigen is contained in the second part, the vaccine antigen can be efficiently delivered to the epidermal layer of the skin. Moreover, since the third layer comprises a water-soluble stringy polymeric substance, which is a base, and has no vaccine antigen, even if the entire third layer does not penetrate into the skin, an antigen such as a vaccine will be fully taken into the body without any loss.
The technique of Patent Literature 8 is a microneedle array for a vaccine in which an antigen is one selected from the group consisting of an influenza hemagglutinin (HA) antigen, tetanus toxoid, diphtheria toxoid, and a recombinant HBs protein. Moreover, in this Patent Literature 8, an example of a microneedle patch for Tetanus and Diphtheria combined vaccine and an example of a microneedle patch for triple vaccine are disclosed.
In the production method of the microneedle patch, an aqueous solution containing a medicinal component is loaded into a microneedle-shaped mold, and dried. Then an aqueous substrate solution is loaded into the mold and the whole molded body is taken off to obtain a patch product. Moreover, a case where a drug is loaded on microneedles by a dipping method is disclosed.
In Non-patent Literature 1, a method is disclosed in which a polymer sheet having projections is produced using a water-soluble polymer and a drug is applied onto the projecting portions with a micropipette. That is, a drug is not contained in a microneedle.